US 12,404,248 B2
IRE1 small molecule inhibitors
Joseph P. Vacca, Telford, PA (US); and Sarah Elizabeth Bettigole, New York, NY (US)
Assigned to Cornell University, Ithaca, NY (US)
Filed by Cornell University, Ithaca, NY (US)
Filed on Jan. 12, 2024, as Appl. No. 18/411,842.
Application 18/411,842 is a continuation of application No. 17/296,771, granted, now 11,945,784, previously published as PCT/US2019/063920, filed on Dec. 2, 2019.
Claims priority of provisional application 62/774,789, filed on Dec. 3, 2018.
Prior Publication US 2024/0287004 A1, Aug. 29, 2024
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 239/42 (2006.01); C07D 213/76 (2006.01); C07D 401/06 (2006.01); C07D 403/06 (2006.01)
CPC C07D 239/42 (2013.01) [C07D 213/76 (2013.01); C07D 401/06 (2013.01); C07D 403/06 (2013.01)] 27 Claims
 
1. A method to treat cancer, the method comprising administering to a subject in need thereof a compound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof, or a pharmaceutical composition thereof

OG Complex Work Unit Chemistry
wherein,

OG Complex Work Unit Chemistry
is C3-C10cycloalkyl;
each R1 is independently —OR6a, —SR6a, —S(═O)R7, —S(═O)2R7, or —N(R6b)2;
each R2 is independently halogen, —CN, -OR8a, —SR8a, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R8b)2, —NR8aS(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R8a, —OCO2R9, —N(R8b)2, —OC(═O)N(R8b)2, —NR8aC(═O)R9, —NR8aC(═O)OR9, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Y5 is CR4,
Y1, Y2, Y3, and Y4 are each independently selected from N and CR5 with the proviso that no more than two of Y1, Y2, Y3, and Y4 are N;
each R6a is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, -X-optionally substituted C1-C4alkyl, -X-optionally substituted C1-C4heteroalkyl, -X-optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C4cycloalkylC1-C3alkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R6b is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, -X-optionally substituted C1-C4alkyl, -X-optionally substituted C1-C4heteroalkyl, -X-optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C3-C4cycloalkylC1-C3alkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R6b are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
X is —C(═O)—;
each R7 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R8a is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R8b is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or two R8b are taken together with the N atom to which they are attached to form an optionally substituted heterocycle;
each R9 is independently optionally substituted C1-C4alkyl, optionally substituted C1-C4heteroalkyl, or optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
A2 is N or CRA;
RA is H, halogen, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted aryl, or —OR10;
RA1, RA2, RA3 and RA4 are each independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, or optionally substituted aryl;
R10 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

OG Complex Work Unit Chemistry
is phenylene or a 6-membered heteroarylene ring comprising 1 or 2 nitrogen atoms in the ring;
B is

OG Complex Work Unit Chemistry
each R3 is independently halogen, —CN, -OR11, —SR11, —N(R11)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R11 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
n is 0, 1, 2, 3, or 4;
p is 1, 2, or 3;
q is 0, 1, 2, or 3;
R4 and each R5 are each independently H, halogen, —CN, -OR12, —SR12, —N(R12)2, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R12 is independently H, optionally substituted C1-C4alkyl, optionally substituted C1-C4fluoroalkyl, optionally substituted C1-C4heteroalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C10heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.